ABSTRACT This application is to continue our studies of Diet and Lifestyle Factors Reducing Risk for Age-Related Eye Disease and addresses the National Eye Institute's priority for research to Delineate the interacting roles of the environment and genetics as risk factors for retinal disease. Unique to these studies is the assessment of the importance of vitamin D status, carotenoid status and scores on broad healthy diet patterns. This is the largest sample, world-wide, that incorporates both eye photographs which document stages of age-related macular degeneration and measurements of the density of the carotenoids in the macula of the eye, where this condition develops. Previous funding has permitted the collection of the most comprehensive set of nutritional data available to evaluate as predictors of lower prevalence of age-related macular degeneration (AMD), an average of six-years later in women 50-79 years of age from three US states in the Carotenoids in Age- Related Eye Disease Study (N=1,787). Because eye photographs identify early changes, before most women are aware of their presence, we were able to study modifiable dietary and lifestyle habits during periods of time when they are likely to influence early stages. We recently reported evidence to support protective roles of vitamin D, the macular carotenoids, lutein and zeaxanthin, healthy diet patterns and physical activity against the development of early/intermediate stages of AMD. There is strong evidence that these early changes are highly predictive of developing advanced stages. However, these previous estimates are averages of the strength of associations across people who differ in genetic propensity for developing AMD. This project, which is ancillary to the Women's Health Initiative, has access to DNA from stored blood samples which we will use to characterize women for high risk genotypes which have strongly predicted risk for AMD in recent large studies and to characterize women with good status of vitamin D and retinal carotenoids. We will use these data to calculate genetic risk rank scores reflect level of overall genetic susceptibility to AMD. We will then evaluate whether the strengths of associations of healthy diets and lifestyles to AMD in people who have high, genetic risk rank scores, compared with women who have low scores. These insights about the range of importance of nutritional factors based on genetic susceptibility will help identify strategies that physicians and public health officials can use to inform people of diets that may lower risk for developing and worsening AMD, to target people who will benefit most, and to motivate people to adopt preventive strategies. The addition of genotyping for candidate genes which have recently been related to the status of carotenoids and vitamin D may also suggest new genetic predictors of AMD and provide insights about mechanisms by which lutein and zeaxanthin, and vitamin D, protect against AMD.